Selective synthesis of meta-phenols from bio-benzoic acids via regulating the adsorption state

Summary Phenols are important building blocks widely applied in many fields. The pronounced orientational effect of the phenolic hydroxyl group makes achieving selective synthesis of meta-phenols challenging. Accessing meta-phenols needs lengthy synthetic sequences. Herein, we first developed a heterogeneous CO2-mediated CeO2-5CuO catalyst for decarboxylative oxidation of benzoic acids with a more than 80% selectivity to meta-phenols. This technology is based on a traceless directing group relay method. The CeO2-CuO catalysts with different Ce/Cu ratios exhibited controllable reaction selectivity between decarboxylation and decarboxylative oxidation. Spectroscopy experiments and computational studies showed the adsorption state of benzoic acid was found to be crucial for subsequent reaction pathways. The moderate adsorption on CO2-mediated CeO2-5CuO catalyst contributes to the distinct selectivity of phenol. Furthermore, the paddlewheel intermediate facilitates the synthesis of meta-phenols from benzoic acids. This traceless directing group method would promote the development of useful one-pot meta-substituted phenols from bio-based benzoic acids.


INTRODUCTION
Phenolic chemicals are essential building blocks and functional moieties in a wide range of chemical and material industries, including pharmaceuticals, agrochemicals, and polymers, owing to their versatile nature and unique properties. [1][2][3] Therefore, the development of strategies for the efficient selective functionalization of specific ring positions in phenols is of great interest to the chemical industry, offering promising avenues for the production of high-value products. Due to the excellent ortho/para orientation ability of the electrondonating phenolic hydroxyl group, various advanced technologies for the synthesis of the ortho/para functionalized phenol have been developed. 4,5 This strong orientation effect, however, limits achieving selectivity in the synthesis of phenols substituted at the meta position. Over the past few decades, several effective strategies, including steric hindrance and directing-group control, have been developed and widely utilized for the efficient synthesis of meta-phenols. [6][7][8][9] However, the practical implementation of these strategies is frequently limited by the need for interconversions involving the installation and removal of directing groups that can impede the formation of meta-substituted phenols. In addition, the competition between the orienting groups often leads to the formation of complex mixtures in molecules bearing multiple electronically or sterically active substituents. Moreover, the above strategies are generally homogeneous catalysis for the production of meta-phenols, which faces a great challenge in industrial manufacture, including separation from products, recycling, and preventing catalyst decomposition during the purification steps. 10 Therefore, the establishment of a heterogeneous catalytic system that enables the direct synthesis of meta-phenols using readily available building blocks would be a highly attractive goal.
On the other hand, benzoic acids (BAs) are abundant and stable chemicals. Recent studies show they can also be produced from the biomass platform [11][12][13][14][15] or degradation of polystyrene. 16 Therefore, an approach to transform BAs into phenols will be a potential method for commercial phenols production from biomass or plastics platforms. However, the implementation of this strategy is complicated by the high energy barrier associated with decarboxylation, as well as the challenges associated with achieving optimal reaction conditions for C-O bond formation. 17 In 2021, Ritter et al. developed the first decarboxylative hydroxylation of BAs to synthesize phenols under mild conditions via radical decarboxylative carbometallation. 18 However, this strategy is still used for the production of most ortho-phenols rather than meta-phenols.
Recently, to overcome these challenges, researchers have developed a decarboxylative oxygenation method that selectively converted BAs to phenols through acid-promoted [1,2]-migration. 19 To synthesize meta-phenols, meta-iodobenzoic acid was utilized to synthesize a range of meta-phenols via three distinct synthetic operations/purifications. Moreover, this process needs strong acid, oxidant, and environmentally unfriendly solvents, which is not favorable to the sustainable production of meta-substituted phenols. Following our recent development of copper-catalyzed oxidative cleavage of aromatic ketone and acid, [20][21][22][23] we proposed that meta-substituted phenols could be formed from BAs by selective decarboxylative oxidation on Cu-based heterogeneous catalyst (Scheme 1).
For heterogeneous catalysts, the adsorption state of the substrate is crucial for the subsequent reaction pathway. Although CuO-based catalysts have been used for synthesizing phenol from BA (Dow phenol process), [24][25][26][27] simple decarboxylation of BA to benzene and overoxidation of product, as side reactions, are still challenges for the high selectivity to phenol. The reported works usually focused on the screening of catalysts and optimization of operating factors. [28][29][30] More importantly, BAs with substituents are more likely to decarboxylation to form arenes, [31][32][33][34] which makes selective decarboxylative oxidation of substituted BAs remain technically elusive thus far. Therefore, we focus on how to suppress the decarboxylation as side reaction in this work. Considering that the formation of a unique paddlewheel intermediate in the decarboxylative oxidation pathway 35-37 is quite different from the benzoate in the decarboxylation pathway, [31][32][33][34] we suppose that it is a potential strategy to change the reaction pathway by regulating the substrate adsorption state. Herein, the adsorption state of BA on a CuO-based catalyst is regulated by the introduction of the CeO 2 component to CuO and CO 2 treatment. We find that the CO 2 -mediated CeO 2 -5CuO catalyst exhibits more than 80% selectivity to phenols in the decarboxylative oxidation reaction of BAs. Further spectroscopy experiments and computational studies illustrate the specific adsorption state of BA and verify its vital effect on product selectivity. Furthermore, the paddlewheel intermediate would generate ortho-salicylate benzoate, which facilitates the synthesis of meta-substituted phenols from ortho or para-substituted BAs.

Catalytic performance of CuO-based catalysts
To improve the phenol selectivity, we try to change the adsorption state of BA by introducing other metallic oxides (MO). In this work, CuO-based catalysts (MO-CuO) were initially synthesized by using an oxalate co-precipitation method (see STAR methods section for catalyst preparation and labeling). The catalytic performance

OPEN ACCESS
of the decarboxylative oxygenation reaction of BA was evaluated at 250 C under an Ar atmosphere for 12 h. As shown in Figure 1A, CuO showed a 31.4% conversion of BA and 51.7% selectivity to phenol. The main by-product, benzene, was generated from the decarboxylation of BA. The conversion of BA and product yield were mainly limited by the additive amount of CuO-based catalyst. Then CuO-based mixed oxides (MO-5CuO, M = Mg, Ce, Zr, Al, Mn) were tested to identify the effect of surface acid-base properties on phenol selectivity. MgO-5CuO and ZrO 2 -5CuO exhibited higher selectivity (62.1% and 55.2%, respectively), but the conversion of BA decreased. Al 2 O 3 -5CuO and MnO 2 -5CuO cannot promote phenol selectivity. CeO 2 -5CuO provided a higher BA conversion (34.7%) and maintained the phenol selectivity (50.2%) as CuO. It seemed that introducing alkaline metal oxides to CuO may increase the phenol selectivity while decreasing the conversion of BA, but CeO 2 exhibited the difference. Therefore, we further investigated CeO 2 -CuO catalysts with different Ce/Cu molar ratios ( Figure 1B). With the increase of Ce/Cu molar ratios to 5 (5CeO 2 -CuO), the selectivity to phenol decreased, and benzene was the main product with 78.4% selectivity. Furthermore, CeO 2 only showed a small benzene yield (2.6%). This may be attributed to the strong adsorption of the carboxyl group in BA at the basic sites of CeO 2 , leading to the decarboxylation reaction. 38,39 Therefore, it can be concluded that the addition of CeO 2 in CuO promotes the decarboxylation reaction of BA to benzene.
To cap the strong base sites, CeO 2 -CuO catalysts were treated with CO 2 at 300 C for 1 h prior to the reaction (labeled as CeO 2 -CuO-CO 2 ). As shown in Figure 1C, phenol selectivity increased on CeO 2 -5CuO-CO 2 and 5CeO 2 -CuO-CO 2 catalysts compared with those without CO 2 treatment. Actually, these results were attributed to the suppression of the by-product benzene, as illustrated in Figures S1 and S2. In addition, only CO 2 can be detected, and no other carbon-containing gas was found ( Figure S3), which indicated that a decarboxylation reaction is involved in the process. Similarly, no product was detected catalyzed by CeO 2 -CO 2 . However, there was no obvious difference in catalytic activities between pristine CuO and CuO-CO 2 . This result suggested that the surface base properties of CuO cannot be regulated by CO 2 treatment because there were no adsorption sites for CO 2 on CuO. Overall, the CeO 2 -5CuO-CO 2 catalyst showed the highest phenol selectivity (78.6%) and yield (15.8%) among the mentioned catalysts. The above results indicate that CO 2 treatment may improve reaction selectivity by capping the base sites on CeO 2 .

Characterization of CeO 2 -5CuO catalyst
To study the components and structure of the CeO 2 -5CuO catalyst, we performed some characterizations. As shown in Figures 2A and 2B, the TEM and HRTEM images indicate that the CeO 2 -5CuO is mainly with the corresponding dominant crystal planes. X-ray photoelectron spectra (XPS) of the CeO 2 -5CuO catalyst show that the valence state of Cu is +2, and the valence state of Ce is +4, with a small part of +3 due to the existence of oxygen vacancies ( Figure S4). The XPS results are consistent with those from TEM and XRD. To figure out the effect of CO 2 treatment on CeO 2 -5CuO catalyst, we also studied the XPS spectra of CeO 2 -5CuO-CO 2 ( Figure S8). The Ce 3d XPS spectra showed that the percentage of Ce 3+ was 25.2% in CeO 2 -5CuO ( Figure S4), and decreased to 15.8% in CeO 2 -5CuO-CO 2. This result was due to the adsorption of CO 2 and then formation of CO 3 2À at oxygen vacancies of CeO 2 , which has been widely reported before. [40][41][42][43] Furthermore, the Lewis base properties of CeO 2 were observed to be produced by the Ce 3+ on the surface. [44][45][46] Therefore, the surface base sites of CeO 2 -5CuO catalyst were finally modified by CO 2 treatment as we expected.

Spectroscopy and computational studies on substrate adsorption state
Diffuse reflectance Fourier transform infrared spectroscopy (DRIFTS) and Raman spectroscopy were then carried out to elucidate the specific BA adsorbates on the surface of different CeO 2 -CuO catalysts, which were crucial for the reaction mechanism. The CeO 2 -5CuO-CO 2 , instead of CeO 2 -5CuO, was chosen to study in contrast to CuO and CeO 2 , because CO 2 treatment of catalyst is a determinant process for improving phenol selectivity. As illustrated in Figure 3, the IR peak located at 1678 cm À1 is identified as the asymmetric stretching mode of COOH of the absorbed BA, while the band observed at 1551 cm À1 corresponds to the antisymmetric stretching vibration of COO À of the absorbed benzoate. [47][48][49][50][51][52] The DRIFTS spectra at 25 C ( Figure 3A) showed that both signals of COOH and COO À were observed on CeO 2 -5CuO-CO 2 , but only COOH signals were observed on CuO, and only COO À signals on CeO 2 . The results indicate that the forms of absorbed BA on CuO and CeO 2 are totally different. The formation of benzoate on CeO 2 is reported to result from the strong adsorption of BA on base sites over CeO 2 . 46,53,54 The spectra of CeO 2 -5CuO-CO 2 at 25 C seem to be a combination of CuO and CeO 2 , but results at 250 C ( Figure 3B) show much different. The signals of COO À were not detected on CeO 2 -5CuO-CO 2 at 250 C. To further  Figure 3D), and CeO 2 -5CuO-CO 2 ( Figure 3E) were studied. The signals of COO À on CeO 2 -5CuO-CO 2 gradually weaken with the increase in temperature, and completely disappear at 200 C. But the signals of COO À on CeO 2 showed no obvious change. The signals of COOH were both observed on CuO and CeO 2 -5CuO-CO 2 .
In addition, the Raman spectra verified the existence of COO À on CeO 2 and CeO 2 -5CuO-CO 2 at 25 C (Figure 3F). Summarizing the information of the DRIFTS and Raman spectra, it could be deduced that the benzoate is easy to form on CeO 2 and hold at 250 C due to the strong adsorption, while the adsorbed BA maintains the molecular state on CuO. The CeO 2 -5CuO-CO 2 catalyst shows moderate adsorption of BA, which may be attributed to the combined effect of introducing CeO 2 component and CO 2 treatment.
To further understand the molecular adsorption states of BA on CeO 2 before and after CO 2 treatment, density functional theory (DFT) calculations were further performed. Two forms of adsorbed BA, molecular (PhCOOH*) and benzoate (PhCOO*), were examined on the (111) surface of CeO 2 with O vacancy. The optimized adsorption states and adsorption energy (E ads ) values are shown in Figure 4, respectively. The distinct difference of E ads (À1.43 eV vs. À5.13 eV) demonstrates the much stronger adsorption of benzoate on raw CeO 2 (111) surface ( Figures 4A and 4B). Then CO 2 was introduced to the CeO 2 (111) to simulate the CO 2 treatment catalysts. The decreased E ads values of two adsorbates indicate the relatively moderate adsorption on CO 2 adsorbed CeO 2 , and both the two forms are reasonable to exist because of the similar E ads values ( Figures 4C and 4D). These results are consistent with those from the DRIFTS and Raman tests. Control experiments were carried out to clarify the influence of the adsorption state of BA on the subsequent reaction pathways (Scheme 2). The above catalytic performance and spectroscopy results suggest that the dissociation of carboxyl to form benzoate leads to the production of benzene. Therefore, lithium benzoate was used as the substrate, and the obviously increased selectivity of benzene (78%) confirmed our deduction (Scheme 2A). Kinetic isotope effect (KIE) experiments were also carried out (Scheme 2B). BA with deuterated carboxyl was reacted under standard conditions, in contrast to the undeuterated BA substrate. The k H /k D = 1.76 of benzene indicated proton dissociation in carboxyl affecting the rate of decarboxylation, while the k H /k D = 0.94 of phenol showed no obvious KIE in decarboxylative oxidation. Furthermore, a physical mixture of CeO 2 with CuO (CeO 2 +5CuO) as the catalyst was tested (Scheme 2C). CO 2 treatment of the physically mixed catalyst showed no influence on product selectivity. This phenomenon demonstrates the synergistic effect of CeO 2 and CuO, adsorption and catalytic conversion, respectively.
Based on the above results, the reaction pathway for this adsorption-regulated decarboxylative oxidation process was proposed (Scheme 3). Basically, the dissociation of carboxyl in BA to form benzoate promotes the decarboxylation to generate benzene, which was reported in previous work [31][32][33][34] and also confirmed by our experiment results. The proton dissociation of BA in water at 250 C results in about 50% selectivity to benzene on CuO (Route A). The introduction of the CeO 2 component achieves strong adsorption of BA on the catalyst, but the base sites on CeO 2 lead to benzoate adsorption (Route B). The CO 2 -mediated catalysts exhibit moderate adsorption of BA, which is prone to generate the paddlewheel intermediate in the decarboxylative oxidation process (Route C). iScience Article Synthesis of meta-substituted phenols from benzoic acids According to Route C in Scheme 3, paddlewheel intermediate (ortho salicylate benzoate) was formed, which inspired us to synthesize the meta-substituted phenols from para or ortho substituted BAs. It is challenging to get meta-substituted phenols from conventional meta-functionalization of phenols because the meta C-H of phenols is not electronically activated. 55 Therefore, decarboxylative oxidation of BAs becomes an alternative method. Based on our above results, the CO 2 -mediated CeO 2 -5CuO catalyst was applied to the synthesis of meta-substituted phenols from BAs. As illustrated in Scheme 4, BAs bearing electronneutral, electron-donating, and electron-withdrawing substituents were selectively transformed into the meta-substituted phenols under standard conditions for 12 h. The meta-phenols could be produced from para-substituted BAs with more than 80% selectivity, or from ortho-substituted BAs with more than 70% selectivity. Most notably, substituted BAs, such as methoxy BAs, are also reported to be produced from lignin oxidative depolymerization, which provides a sustainable method to synthesize metasubstituted phenols.
To be mentioned, the relatively low conversion was due to the deactivation of the catalyst and further XRD ( Figure S5), XPS ( Figure S6) and AES ( Figure S7) studies of the used catalyst showed that it was caused by the reduction of Cu(II) to Cu(I) on the surface. Satisfyingly, the catalyst can be reactivated by simply calcined at 400 C in air. The reuse test showed that the CeO 2 -5CuO-CO 2 catalyst could be used at least four times without an obvious decrease in activity and selectivity ( Figure 5). The facile catalyst regeneration and stable catalytic performance make this strategy promising for industrial-scale decarboxylation of benzoic acid to produce meta-substituted phenols.

Conclusion
In conclusion, we report a heterogeneous CO 2 -mediated CeO 2 -5CuO catalyst for decarboxylative oxidation of BAs, which facilitates the one-pot synthesis of meta-substituted phenols with more than 80% selectivity. This technology is based on a traceless directing group relay method. This selective procedure avoids the otherwise typical formation of benzene by-product via decarboxylation. DFT calculations and experimental investigations showed that the adsorption states of BA could be regulated by the iScience Article introduction of CeO 2 component and CO 2 treatment, which are determinants for subsequent reaction pathways. Furthermore, CO 2 -mediated CeO 2 -5CuO catalyst after facile regeneration still has stable catalytic performance. Due to the abundance of BAs and the importance of phenols, the technology is expected to have broad applications in organic synthesis.

Limitations of the study
The main content of our work is the synthesis of meta-substituted phenols from biomass-based BAs. However, the CeO 2 -5CuO catalyst needs to be regenerated under air atmosphere at 300 C after one time use under standard reaction conditions (250 C, 12 h, 1 mmol substrate). Further studies are ongoing to improve the stability of catalysts. In addition, the regeneration process may be facile to conduct in a fixed-bed reactor.

STAR+METHODS
Detailed methods are provided in the online version of this paper and include the following:

DECLARATION OF INTERESTS
The authors declare no competing interests.

INCLUSION AND DIVERSITY
We support inclusive, diverse, and equitable conduct of research.

Catalyst characterization
Transmission electron micrographs (TEM) were obtained on a JEM-2100 microscope operated at 200 kV. The samples were suspended in ethanol, and a few drops of the suspension were dried to the TEM grid for TEM measurement. X-ray diffractograms of the samples were obtained on a Malvern Panalytical Empyream Powder X-ray diffractometer with Cu Ka radiation. The measurement was operated at 40 kV and scanning 2q from 5 to 80 with a step of 0.013 . The signal was collected by a pixel 1D detector, and the data were analyzed by comparison with reference patterns in the database (PDF2-2004). X-ray photoelectron spectra (XPS) were recorded on a Thermo Scientific Escalab 250 Xi equipped with a monochromatic Al Ka X-ray radiation source (hn = 1486.6 eV). The C 1s peak was used as the reference at 284.8 eV. Diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) spectra of adsorbed BA on catalysts were collected in an in-situ reaction cell on a Thermo Scientific Nicolet iS50 equipped with an MCT detector. Prior to analysis, the catalyst was added to the benzoic acid aqueous solution at 100 C for 1 h and then washed with ethanol three times. The obtained solid was dried at 80 C overnight under a vacuum to get BA adsorbed catalyst. DRIFT spectra were recorded after the reaction cell was purged with Ar for 10 min to remove the air. The background and catalyst sample spectra were scanned 64 times at one set with a 4 cm À1 resolution. Raman spectra were collected with a 532 nm constant-wave laser (Bruker Optics) that served as the excitation source.

Catalytic evaluation
Catalytic reactions were carried out in a 50 mL stainless steel batch reactor from Beijing Century Senlong Experimental Apparatus Co. Ltd. The reactor was equipped with a magnetic stirrer, a thermocouple, a pressure gauge, and a programmable controller. In a typical run, 1 mmol of benzoic acid, 20 mL of H 2 O, and 1 mmol of Cu-based catalyst were loaded into the reactor. The reactor was purged with Ar for 10 min to remove the air. The reactor was then heated to 250 C and kept for a specified reaction time while the content was stirred at a rate of 600 rpm. After the reaction, the liquid was extracted with 20 mL ethyl acetate three times and 73.8 mg of n-dodecane as an internal standard was added into the organic phase. The reaction products were identified by GC-MS (Agilent 7890A-5975C) and quantified by GC (Agilent 7890B) with a flame ionization detector (FID) using an HP-INNOWax column.
The conversion of benzoic acid (conv.), selectivity of product (sel.) and product yield were calculated by Equations 1, 2 and 3, respectively. In these equations, n initial BA and n final BA are the molar amount of benzoic acid before and after reaction. n product i is the molar amount of product i in the reaction mixture. n total product is the total molar amount of products in the reaction mixture.

Computational method
We have employed the Vienna Ab Initio Package (VASP) 56,57 to perform all the density functional theory (DFT) calculations within the generalized gradient approximation (GGA) using the PBE 58 formulation. We have chosen the projected augmented wave (PAW) potentials 59